DESCRIPTION (Applicant's abstract): The mammalian carotid body, an arterial chemosensory organ, is comprised of specialized chemosensory type I cells and supportive type II cells embedded in a dense network of fenestrated capillaries and sinusoids. In response to natural stimuli (e.g., hypoxia, hypercapnia), type I cells release multiple neurotransmitter agents which excite chemoafferent nerve terminals of the carotid sinus nerve. The carotid body is the primary sensor for dissolved O2 in arterial blood, and as such, it is essential for the ventilatory acclimatization, which occurs during prolonged exposure to high altitude, and in a variety of other physiological and pathological states involving acute and chronic hypoxemia. In response to chronic hypoxia (CH), the carotid body undergoes remarkable morphological changes, including hypertrophy and hyperplasia of type I cells, and a dramatic increase in blood vessel volume (neo-vascularization). In addition, there is a gradual increase in chemosensitivity to hypoxia. Virtually nothing is known about the cellular mechanisms, which mediate these changes. Based upon our preliminary data, we hypothesize that four substances, all endogenous to the carotid body, are intimately involved in the tissue remodeling and reshaping as well as the increased chemosensitivity, which occurs during CH. These substances are vascular endothelial growth factor (VEGF), endothelin (ET), atrial natriuretic peptide (ANP) and nitric oxide (NO). They have in common vascular, mitogenic and neuro-regulatory properties. Using molecular biological, immunocytochemical, electrophysiological and neurochemical techniques, our proposed studies will explore: I. The effects of CH on the expression of these four substances and their receptors in the carotid body; II. Their role in tissue growth and tissue remodeling in the CH carotid body; III. Their up-regulation and contribution to the altered chemosensitivity which follows CH; and IV. The effects of CH on the cellular signaling mechanisms mediated by VEGF, ET, ANP and NO in this chemoreceptive tissue.